LYNPARZA Has the Potential to Offer a New
Treatment Option for Patients with Germline BRCA-Mutated,
HER2-Negative Metastatic Breast Cancer
Regulatory Submission Acceptance Is the
First for a PARP Inhibitor Beyond Ovarian Cancer
AstraZeneca and Merck (NYSE:MRK), known as MSD outside the
United States and Canada, today announced that the U.S. Food and
Drug Administration (FDA) has accepted and granted priority review
for a supplemental New Drug Application (sNDA) for the use of
LYNPARZA® (olaparib) tablets in patients with germline BRCA-mutated
(gBRCA), HER2-negative metastatic breast cancer (MBC) who have been
previously treated with chemotherapy either in the neoadjuvant,
adjuvant or metastatic settings. A Prescription Drug User Fee Act
(PDUFA) date is set for the first quarter of 2018.
This is the first submission for a poly ADP-ribose polymerase
(PARP) inhibitor outside ovarian cancer and the third indication
submission for LYNPARZA in the U.S. The sNDA is based on the
positive results from the phase 3 OlympiAD trial published in the
New England Journal of Medicine.
LYNPARZA was first approved under the FDA’s Accelerated Approval
program in December 2014, as a capsule formulation, making it the
first PARP inhibitor ever approved. Since then, more than 3,000
advanced ovarian cancer patients have been treated with LYNPARZA.
LYNPARZA tablets are currently being tested in a range of tumor
types, including breast, prostate and pancreatic cancers.
LYNPARZA tablets are currently approved in the U.S. as a
maintenance treatment for adult patients with recurrent, epithelial
ovarian, fallopian tube or primary peritoneal cancer who are in a
complete or partial response to platinum-based chemotherapy,
regardless of BRCA status. The medicine is also indicated for use
in adult patients with deleterious or suspected deleterious
gBRCA-mutated advanced ovarian cancer, who have been treated with
three or more prior lines of chemotherapy; patients for this
indication are selected for therapy based on an FDA-approved
companion diagnostic.
IMPORTANT SAFETY INFORMATION
DOSING AND ADMINISTRATION
To avoid substitution errors and overdose, do not substitute
LYNPARZA (olaparib) tablets with LYNPARZA capsules on a
milligram-to-milligram basis due to differences in the dosing and
bioavailability of each formulation. Recommended tablet dose is 300
mg, taken orally twice daily, with or without food. Continue
treatment until disease progression or unacceptable toxicity. For
adverse reactions, consider dose interruption or dose
reduction.
WARNINGS AND PRECAUTIONS
There are no contraindications for LYNPARZA.
Myelodysplastic Syndrome/Acute Myeloid Leukemia
(MDS/AML): Occurred in <1.5% of patients exposed to
LYNPARZA monotherapy, and the majority of events had a fatal
outcome. The duration of therapy in patients who developed
secondary MDS/AML varied from <6 months to >2 years. All of
these patients had previous chemotherapy with platinum agents
and/or other DNA-damaging agents, including radiotherapy, and some
of these patients also had a history of previous cancer or bone
marrow dysplasia.
Do not start LYNPARZA until patients have recovered from
hematological toxicity caused by previous chemotherapy (≤Grade 1).
Monitor complete blood counts for cytopenia at baseline and monthly
thereafter for clinically significant changes during treatment. For
prolonged hematological toxicities, interrupt LYNPARZA and monitor
blood counts weekly until recovery. If the levels have not
recovered to Grade 1 or less after 4 weeks, refer the patient to a
hematologist for further investigations, including bone marrow
analysis and blood sample for cytogenetics. Discontinue LYNPARZA if
MDS/AML is confirmed.
Pneumonitis: Occurred in <1% of patients exposed
to LYNPARZA, and some cases were fatal. If patients present with
new or worsening respiratory symptoms such as dyspnea, cough, and
fever, or a radiological abnormality occurs, interrupt treatment
with LYNPARZA and initiate prompt investigation. Discontinue
LYNPARZA (olaparib) if pneumonitis is confirmed and treat patient
appropriately.
Embryo-Fetal Toxicity: Based on its mechanism of
action and findings in animals, LYNPARZA can cause fetal harm. A
pregnancy test is recommended for females of reproductive potential
prior to initiating treatment. Advise females of reproductive
potential of the potential risk to a fetus and to use effective
contraception during treatment and for 6 months after receiving the
final dose.
ADVERSE REACTIONS—Maintenance Setting
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in clinical trials of LYNPARZA in the maintenance
setting for SOLO-2: nausea (76%), fatigue
(including asthenia) (66%), anemia (44%), vomiting (37%),
nasopharyngitis/upper respiratory tract infection (URI)/influenza
(36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%),
headache (26%), decreased appetite (22%), and stomatitis (20%).
Study 19: nausea (71%), fatigue (including asthenia)
(63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory
tract infection (22%), constipation (22%), headache (21%), and
decreased appetite (21%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA in the maintenance
setting (SOLO-2/Study 19) were: increase in mean corpuscular
volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in
leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease
in absolute neutrophil count (51%/47%), increase in serum
creatinine (44%/45%), and decrease in platelets (42%/36%).
ADVERSE REACTIONS—Advanced gBRCAm ovarian cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in clinical trials of LYNPARZA for advanced gBRCAm ovarian
cancer after 3 or more lines of chemotherapy (pooled from 6
studies) were: fatigue (including asthenia) (66%), nausea (64%),
vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper
respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia
(22%), decreased appetite (22%), and arthralgia/musculoskeletal
pain (21%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA for advanced gBRCAm
ovarian cancer after 3 or more lines of chemotherapy (pooled
from 6 studies) were: decrease in hemoglobin (90%), increase in
mean corpuscular volume (57%), decrease in lymphocytes (56%),
increase in serum creatinine (30%), decrease in platelets (30%),
and decrease in absolute neutrophil count (25%).
DRUG INTERACTIONS
Anticancer Agents: Clinical studies of LYNPARZA
(olaparib) in combination with other myelosuppressive anticancer
agents, including DNA-damaging agents, indicate a potentiation and
prolongation of myelosuppressive toxicity.
CYP3A Inhibitors: Avoid concomitant use of strong or
moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor
must be co-administered, reduce the dose of LYNPARZA. Advise
patients to avoid grapefruit, grapefruit juice, Seville oranges,
and Seville orange juice during LYNPARZA treatment.
CYP3A Inducers: Avoid concomitant use of strong or
moderate CYP3A inducers when using LYNPARZA. If a moderate inducer
cannot be avoided, be aware of a potential for decreased efficacy
of LYNPARZA.
USE IN SPECIFIC POPULATIONS
Pediatric Use: The safety and efficacy of LYNPARZA have
not been established in pediatric patients.
Lactation: No data are available regarding the
presence of olaparib in human milk, the effects on the breastfed
infant, or the effects on milk production. Because of the potential
for serious adverse reactions in the breastfed infant, advise a
lactating woman not to breastfeed during treatment with LYNPARZA
and for 1 month after receiving the final dose.
Hepatic Impairment: No adjustment to the starting
dose is required in patients with mild hepatic impairment
(Child-Pugh classification A). There are no data in patients with
moderate or severe hepatic impairment.
Renal Impairment: No adjustment to the starting dose
is necessary in patients with mild renal impairment (CLcr
51-80 mL/min). In patients with moderate renal
impairment (CLcr 31-50 mL/min), reduce the dose to 200 mg
twice daily. There are no data in patients with severe renal
impairment or end-stage renal disease (CLcr ≤30
mL/min).
Please see complete Prescribing
Information, including Patient Information (Medication
Guide)
About OlympiAD
OlympiAD is a randomized, open-label, multicenter phase 3 trial
assessing the efficacy and safety of LYNPARZA (olaparib) tablets
(300mg twice daily) compared to ‘physician’s choice’ chemotherapy
(capecitabine, vinorelbine, eribulin) in 302 patients with
HER2-negative metastatic breast cancer with germline BRCA1 or BRCA2
mutations, which are predicted or suspected to be deleterious. The
international trial was conducted in 19 countries from across
Europe, Asia, North America and South America.
About LYNPARZA® (olaparib)
LYNPARZA was the first FDA-approved oral poly ADP-ribose
polymerase (PARP) inhibitor that may exploit tumor DNA damage
response (DDR) pathway deficiencies to potentially kill cancer
cells. Specifically, in vitro studies have shown that
olaparib-induced cytotoxicity may involve inhibition of PARP
enzymatic activity and increased formation of PARP-DNA complexes,
resulting in DNA damage and cancer cell death.
LYNPARZA is the foundation of AstraZeneca’s industry-leading
portfolio of compounds targeting DDR mechanisms in cancer
cells.
About Metastatic Breast Cancer
Approximately one in eight women are diagnosed with breast
cancer in the U.S. Of these patients, approximately one-third are
either diagnosed with or progress to the metastatic stage of the
disease. Despite treatment options increasing during the past three
decades, there is currently no cure for patients diagnosed with
metastatic breast cancer. Thus, the primary aim of treatment is to
slow progression of the disease for as long as possible, improving
or at least maintaining, a patient’s quality of life.
About Germline BRCA Mutations
BRCA1 and BRCA2 are human genes that produce proteins
responsible for repairing damaged DNA and play an important role
maintaining the genetic stability of cells. When either of these
genes is mutated, or altered, such that its protein product either
is not made or does not function correctly, DNA damage may not be
repaired properly. As a result, cells are more likely to develop
additional genetic alterations that can lead to cancer.
About the AstraZeneca and Merck Strategic Oncology
Collaboration
On July 27, 2017, AstraZeneca and Merck & Co., Inc.,
announced a global strategic oncology collaboration to co-develop
and co-commercialize AstraZeneca’s LYNPARZA (olaparib), the world’s
first and leading PARP inhibitor, and potential new medicine
selumetinib, a MEK inhibitor, for multiple cancer types. The
collaboration is based on increasing evidence that PARP and MEK
inhibitors can be combined with PD-L1/PD-1 inhibitors for a range
of tumor types. Working together, the companies will jointly
develop LYNPARZA and selumetinib in combination with other
potential new medicines and as a monotherapy. Independently, the
companies will develop LYNPARZA and selumetinib in combination with
their respective PD-L1 and PD-1 medicines.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative
oncology medicines to help people with cancer worldwide. At Merck,
helping people fight cancer is our passion and supporting
accessibility to our cancer medicines is our commitment. Our focus
is on pursuing research in immuno-oncology and we are accelerating
every step in the journey – from lab to clinic – to potentially
bring new hope to people with cancer.
As part of our focus on cancer, Merck is committed to exploring
the potential of immuno-oncology with one of the fastest-growing
development programs in the industry. We are currently executing an
expansive research program evaluating our anti-PD-1 therapy across
more than 30 tumor types. We also continue to strengthen our
immuno-oncology portfolio through strategic acquisitions and are
prioritizing the development of several promising immunotherapeutic
candidates with the potential to improve the treatment of advanced
cancers.
For more information about our oncology clinical trials, visit
www.merck.com/clinicaltrials.
About Merck
For more than a century, Merck, a leading global
biopharmaceutical company known as MSD outside of the United States
and Canada, has been inventing for life, bringing forward medicines
and vaccines for many of the world’s most challenging diseases.
Through our prescription medicines, vaccines, biologic therapies
and animal health products, we work with customers and operate in
more than 140 countries to deliver innovative health solutions. We
also demonstrate our commitment to increasing access to health care
through far-reaching policies, programs and partnerships. Today,
Merck continues to be at the forefront of research to advance the
prevention and treatment of diseases that threaten people and
communities around the world - including cancer, cardio-metabolic
diseases, emerging animal diseases, Alzheimer’s disease and
infectious diseases including HIV and Ebola. For more information,
visit www.merck.com and connect with us on
Twitter, Facebook, Instagram, YouTube
and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
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USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
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the products will receive the necessary regulatory approvals or
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